Community-Level Factors are Predictors of Severe Maternal Morbidity Among American Indian and Alaska Native Pregnant People in the Pacific Northwest in a Multilevel Logistic Regression.

INTRODUCTION: American Indian/Alaska Native (AI/AN) pregnant people face barriers to health and healthcare that put them at risk of pregnancy complications. Rates of severe maternal morbidity (SMM) among Indigenous pregnant people are estimated to be twice that of non-Hispanic White (NHW) pregnant people. METHODS: Race-corrected Oregon Hospital Discharge and Washington Comprehensive Hospital Abstract Reporting System data were combined to create a joint dataset of births between 2012 and 2016. The analytic sample was composed of 12,535 AI/AN records and 313,046 NHW records. A multilevel logistic regression was used to assess the relationship between community-level, individual and pregnancy risk factors on SMM for AI/AN pregnant people. RESULTS: At the community level, AI/AN pregnant people were more likely than NHW to live in mostly or completely rural counties with low median household income and high uninsured rates. They were more likely to use Medicaid, be in a high-risk age category, and have diabetes or obesity. During pregnancy, AI/AN pregnant people were more likely to have insufficient prenatal care (PNC), gestational diabetes, and pre-eclampsia. In the multilevel model, county accounted for 6% of model variance. Hypertension pre-eclampsia, and county rurality were significant predictors of SMM among AI/AN pregnant people. High-risk age, insufficient PNC and a low county insured rate were near-significant at p < 0.10. DISCUSSION: Community-level factors are significant contributors to SMM risk for AI/AN pregnant people in addition to hypertension and pre-eclampsia. These findings demonstrate the need for targeted support in pregnancy to AI/AN pregnant people, particularly those who live in rural and underserved communities.

What is already known on this subject? American Indian and Alaska Native pregnant people face higher rates of severe maternal morbidity and mortality, and the risk is exacerbated for rural Indigenous pregnant people.What this study adds? This publication uses a multilevel model to assess the contribution of community-level factors in severe maternal morbidity risk for American Indian and Alaska Native pregnant people. This analysis highlights the important role that rurality, prenatal care adequacy and access to insurance play in maternal morbidity risk and discusses how those risks are disproportionately felt by American Indian and Alaska Native pregnant people in the Pacific Northwest.

White matter hyperintensities and the surrounding normal appearing white matter are associated with water channel disruption in the oldest old.

INTRODUCTION: Age-related magnetic resonance imaging (MRI) T2 white matter hyperintensities (WMHs) are common and associated with neurological decline. We investigated the histopathological underpinnings of MRI WMH and surrounding normal appearing white matter (NAWM), with a focus on astroglial phenotypes. METHODS: Brain samples from 51 oldest old Oregon Alzheimer's Disease Research Center participants who came to autopsy underwent post mortem (PM) 7 tesla MRI with targeted histopathological sampling of WMHs and NAWM. Stained slides were digitized and quantified. Mixed-effects models determined differences in molecular characteristics between WMHs and the NAWM and across NAWM. RESULTS: PM MRI-targeted WMHs are characterized by demyelination, microglial activation, and prominent astrocytic alterations, including disrupted aquaporin (AQP) expression. Similar changes occur within the surrounding NAWM in a pattern of decreasing severity with increased distance from WMHs. DISCUSSION: Decreased AQP expression within WMH and proximal NAWM suggest an overwhelmed system wherein water homeostasis is no longer maintained, contributing to WM damage in older individuals. HIGHLIGHTS: Post mortem magnetic resonance imaging (MRI) was used to characterize the pathology of white matter hyperintensities (WMHs) and surrounding normal appearing white matter (NAWM). Stained immunohistochemical (IHC) slides from targeted WMH and NAWM samples were digitized and quantified. WMHs and NAWM were associated with inflammation, demyelination, and gliosis. WMHs and NAWM astrocytic changes included decreased AQP1 and AQP4 expression. Abnormal NAWM pathology diminished in severity with increasing distance from WMH.

Venous Collagenosis as Pathogenesis of White Matter Hyperintensity.

OBJECTIVE: Periventricular white matter hyperintensities (pvWMHs) are commonly observed on MRI in older individuals and are associated with cognitive and motor decline. The etiology of pvWMH remains unknown. Venous collagenosis has been implicated, which may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). Here, we examine relationships between in vivo pvWMH volume and ex vivo morphological quantification of collagenosis and the PVS in veins and arteries. METHODS: Brain tissue from 25 Oregon Alzheimer's Disease Research Center subjects was selected to cover the full range of WMH burden. Tissue from white matter abutting the ventricle was stained with Masson's trichrome and smooth muscle actin. An automated hue based algorithm identified and segmented vessel into collagenized vessel walls, lumen, and PVS. Multiple linear regressions with pvWMH volume as the dependent variable and either collagen thickness or PVS width were performed with covariates of vessel diameter, age at death, sex, and interval between MRI and death. RESULTS: PVS width and collagen thickness were significantly correlated in both arteries (r = 0.21, p = 0.001) and veins (r = 0.23, p = 0.001). Increased venous collagen (p = 0.017) was a significant predictor of higher pvWMH burden while arterial collagen was not (p = 0.128). Neither PVS width in arteries (p = 0.937) nor veins (p = 0.133) predicted pvWMH burden. INTERPRETATION: These findings are consistent with a model in which venous collagenosis mediates the relationship between vascular risk factors and pvWMH. This study confirms the importance of changes to the venous system in contributing to MRI white matter lesions commonly observed with advanced age. ANN NEUROL 2022;92:992-1000.

Autoidentification of perivascular spaces in white matter using clinical field strength T1 and FLAIR MR imaging.

Recent interest in enlarged perivascular spaces (ePVS) in the brain, which can be visualized on MRI and appear isointense to cerebrospinal fluid on all sequence weightings, has resulted in the necessity of reliable algorithms for automated segmentation to allow for whole brain assessment of ePVS burden. However, several publicly available datasets do not contain sequences required for recently published algorithms. This prospective study presents a method for identification of enlarged perivascular spaces (ePVS) in white matter using 3T T1 and FLAIR MR imaging (MAPS-T1), making the algorithm accessible to groups with valuable sets of limited data. The approach was applied identically to two datasets: 1) a repeated measurement in a dementia-free aged human population (N = 14), and 2) an aged sample of multisite ADNI datasets (N = 30). ePVS segmentation was accomplished by a stepwise local homogeneity search of white matter-masked T1-weighted data, constrained by FLAIR hyperintensity, and further constrained by width, volume, and linearity measurements. Pearson's r was employed for statistical testing between visual (gold standard) assessment and repeated measures in cohort one. Visual ePVS counts were significantly correlated with MAPS-T1 (r = .72, P < .0001). Correlations between repeated measurements in cohort one were significant for both visual and automated methods in the single visually-rated slice (MAPS-T1: r = .87, P < .0001, visual: (r = .86, P < .0001) and for whole brain assessment (MAPS-T1: r = .77, P = .001). Results from each cohort were manually inspected and found to have positive predictive values of 77.5% and 87.5%, respectively. The approach described in this report is an important tool for detailed assessment of ePVS burden in white matter on routinely acquired MRI sequences.

A Review of Oxylipins in Alzheimer's Disease and Related Dementias (ADRD): Potential Therapeutic Targets for the Modulation of Vascular Tone and Inflammation.

There is now a convincing body of evidence from observational studies that the majority of modifiable Alzheimer's disease and related dementia (ADRD) risk factors are vascular in nature. In addition, the co-existence of cerebrovascular disease with AD is more common than AD alone, and conditions resulting in brain ischemia likely promote detrimental effects of AD pathology. Oxylipins are a class of bioactive lipid mediators derived from the oxidation of long-chain polyunsaturated fatty acids (PUFAs) which act as modulators of both vascular tone and inflammation. In vascular cognitive impairment (VCI), there is emerging evidence that oxylipins may have both protective and detrimental effects on brain structure, cognitive performance, and disease progression. In this review, we focus on oxylipin relationships with vascular and inflammatory risk factors in human studies and animal models pertinent to ADRD. In addition, we discuss future research directions with the potential to impact the trajectory of ADRD risk and disease progression.

Postmortem 7T MRI for guided histopathology and evaluation of cerebrovascular disease.

Postmortem (PM) magnetic resonance imaging (MRI) can serve as a bridge between in vivo imaging and histology by connecting MRI observed macrostructural findings to histological staining and microstructural changes. Data were acquired from 20 formalin-fixed brains including T2, T1, PD, and T2*-weighted images of left hemispheres and 6-mm-thick coronal slices. Tissue slices were bisected, aligned to MR images and used to guide histological sampling. Markers of myelin and oligodendroglia alterations were semiquantitatively rated and compared within white matter hyperintensities (WMHs) and normal-appearing white matter. Tissue priors were created from 3T in vivo data and used to guide segmentation of WMH. PM WMH and hemisphere volumes were compared to volumes derived from in vivo data. PM T2 WMH and T1 hemisphere volumes were correlated with in vivo 3T FLAIR WMH and T1 hemisphere volumes. WMH showed significant myelin loss, decreased GFAP expression and increased vimentin expression. MR-visible perivascular spaces and cortical microvascular lesions were successfully captured on histopathological sections. PM MRI can quantify cerebrovascular disease burden and guide tissue sampling, allowing for more comprehensive characterization of cerebrovascular disease that may be used to study etiologies of age-related cognitive change.

Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid ß plaque formation in mice.

BACKGROUND: Slowed clearance of amyloid ß (Aß) is believed to underlie the development of Aß plaques that characterize Alzheimer's disease (AD). Aß is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aß clearance, and promotes Aß plaque formation. METHODS: To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin (Snta1) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid ß levels. RESULTS: In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aß and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid ß levels. CONCLUSIONS: These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.

Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2.

Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI.

Consequences of the COVID-19 Lockdown in Germany: Effects of Changes in Daily Life on Musical Engagement and Functions of Music.

The current study investigated how music has been used during the COVID-19 pandemic and how personal factors have affected music-listening behavior. During the shutdown in Spring 2020 in Germany, 539 participants took part in an online survey reporting on functions of music listening, attributes of listened music, and active engagement with music, retrospectively before and during the pandemic. Next to these implicit questions, participants were asked to describe the changes they explicitly noticed in handling music during COVID-19, their current worries, and their new everyday life during the pandemic as well as personality traits and stress reactivity. A logistic regression model was fitted, showing that people reduced their active engagement with music during the lockdown, and the function of killing time and overcoming loneliness became more important, reflecting the need for distraction and filling the silence. Before the lockdown, music was listened to for the function of motor synchronization and enhanced well-being, which reflects how people have lost both their musical and activity routines during the lockdown. The importance of in-person engagement with music in people's lives became particularly evident in the connection between worries about further restrictions and the need for live music.

Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology.

The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer's disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD.

High fat diet-induced diabetes in mice exacerbates cognitive deficit due to chronic hypoperfusion.

Diabetes causes endothelial dysfunction and increases the risk of vascular cognitive impairment. However, it is unknown whether diabetes causes cognitive impairment due to reductions in cerebral blood flow or through independent effects on neuronal function and cognition. We addressed this using right unilateral common carotid artery occlusion to model vascular cognitive impairment and long-term high-fat diet to model type 2 diabetes in mice. Cognition was assessed using novel object recognition task, Morris water maze, and contextual and cued fear conditioning. Cerebral blood flow was assessed using arterial spin labeling magnetic resonance imaging. Vascular cognitive impairment mice showed cognitive deficit in the novel object recognition task, decreased cerebral blood flow in the right hemisphere, and increased glial activation in white matter and hippocampus. Mice fed a high-fat diet displayed deficits in the novel object recognition task, Morris water maze and fear conditioning tasks and neuronal loss, but no impairments in cerebral blood flow. Compared to vascular cognitive impairment mice fed a low fat diet, vascular cognitive impairment mice fed a high-fat diet exhibited reduced cued fear memory, increased deficit in the Morris water maze, neuronal loss, glial activation, and global decrease in cerebral blood flow. We conclude that high-fat diet and chronic hypoperfusion impair cognitive function by different mechanisms, although they share commons features, and that high-fat diet exacerbates vascular cognitive impairment pathology.

Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia. Reduced cerebral blood flow is thought to play a major role in the etiology of VCI. Therefore, chronic cerebral hypoperfusion has been used to model VCI in rodents. The goal of the current study was to determine the histopathological and neuroimaging substrates of neurocognitive impairments in a mouse model of chronic cerebral hypoperfusion induced by unilateral common carotid artery occlusion (UCCAO). Mice were subjected to sham or right UCCAO (VCI) surgeries. Three months later, neurocognitive function was evaluated using the novel object recognition task, Morris water maze, and contextual and cued fear-conditioning tests. Next, cerebral perfusion was evaluated with dynamic susceptibility contrast magnetic resonance imaging (MRI) using an ultra-high field (11.75 T) animal MRI system. Finally, brain pathology was evaluated using histology and T2-weighted MRI. VCI, but not sham, mice had significantly reduced cerebral blood flow in the right vs. left cerebral cortex. VCI mice showed deficits in object recognition. T2-weighted MRI of VCI brains revealed enlargement of lateral ventricles, which corresponded to areas of hippocampal atrophy upon histological analysis. In conclusion, our data demonstrate that the UCCAO model of chronic hypoperfusion induces hippocampal atrophy and ventricular enlargement, resulting in neurocognitive deficits characteristic of VCI.

Soluble epoxide hydrolase gene deletion improves blood flow and reduces infarct size after cerebral ischemia in reproductively senescent female mice.

Soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilatory epoxyeicosatrienoic acids (EETs), is sexually dimorphic, suppressed by estrogen, and contributes to underlying sex differences in cerebral blood flow and injury after cerebral ischemia. We tested the hypothesis that sEH inhibition or gene deletion in reproductively senescent (RS) female mice would increase cerebral perfusion and decrease infarct size following stroke. RS (15-18 month old) and young (3-4 month old) female sEH knockout (sEHKO) mice and wild type (WT) mice were subjected to 45 min middle cerebral artery occlusion (MCAO) with laser Doppler perfusion monitoring. WT mice were treated with vehicle or a sEH inhibitor t-AUCB at the time of reperfusion and every 24 h thereafter for 3 days. Differences in regional cerebral blood flow were measured in vivo using optical microangiography (OMAG). Infarct size was measured 3 days after reperfusion. Infarct size and cerebral perfusion 24 h after MCAO were not altered by age. Both sEH gene deletion and sEH inhibition increased cortical perfusion 24 h after MCAO. Neither sEH gene deletion nor sEH inhibition reduced infarct size in young mice. However, sEH gene deletion, but not sEH inhibition of the hydrolase domain of the enzyme, decreased infarct size in RS mice. Results of these studies show that sEH gene deletion and sEH inhibition enhance cortical perfusion following MCAO and sEH gene deletion reduces damage after ischemia in RS female mice; however this neuroprotection in absent is young mice.